1. Field of the Invention
The present invention relates to a method of screening for a substance useful for transdifferentiation of microglia into neurons, a method of producing neurons, and a method of treating a neurologic disorder.
2. Background Technology
The regenerative therapy in cerebral and neurological fields refers to the differentiation of cells having the capability to differentiate into neurons and its application to therapy. The cells used have been mainly neural stem cells and ES cells. On the other hand, microglia, one of glia cells in the central nervous system, are considered to be more suitable for use in the regenerative therapy than neural stem cells or ES cells because of, for example, the following reasons: (1) a patient can use his/her own cells, which causes fewer ethical problems, (2) the number of neurons to be differentiated will be large since the number of microglia is extremely large, and (3) there is no need for concern about the migration of differentiated cells toward lesions since microglia themselves have a feature to migrate toward lesions (Imai, F. et al., Neuroscience Letters 272:127-130 (1999), Gehrmann, J. et al., Brain Research Reviews 20:269-287 (1995)). To date, the use of serum has been reported as a means to transdifferentiate microglia into neurons (Yokoyama A. et al., Glia 45(1):96-104 (2004)).
Meantime, bone morphogenetic protein (hereinafter referred to as “BMP”) was originally identified as a protein which controls the formation of cartilage and bone (Wozney J M. et al., Science 242:1528-1534 (1988)). Further, BMP is known to act also on monocytes, epithelial cells, mesenchymal cells, and neural cells and plays a central role in the morphogenesis of various tissues and organs by controlling the growth, differentiation, migration, and apoptosis of these cells (Hogan B L M. et al., Genes Dev 10:1580-1594 (1996)). To date, it has been reported that the signals from the BMP receptor IA are essential for the development of intervening neurons of spinal cord (Wine-Lee L. et al., Development 131:5393-5403 (2004)), that BMP-4 suppresses the production of neurons in the fetal brain (Finleg M F. et al., J. Neurobiol. 40:271-287 (1999)) and that BMP-2 mediates switching from neuron production to astrocyte production (Nakashima K. et al., PNAS 98:5868-5873 (2001)).